(3,4,7,8,9,10-hexahydro-6, 10 -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic-acid derivatives

ABSTRACT

A compound of the formula                    
     wherein R is alkyl or aralkyl of up to 18 carbon atoms, the amine function being optionally protected are used to prepare compounds of the formula                    
     in which R retains its previous meaning and the amine is optionally protected.

This application is a continuation os U.S. Pat. application Ser. No.09/296,325 filed Apr. 22, 1999.

OBJECTS OF THE INVENTION

It is an object of the invention to provide the novel compounds offormula I and a process and intermediates for their preparation.

It is another object of the invention to provide the novel compounds offormula III and a process for their preparation.

These and other objects and advantages of the invention will becomeobvious from the following detailed description.

THE INVENTION

The novel compounds of the invention are compounds of the formula

wherein R is selected from the group consisting of hydrogen, alkyl of 1to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and theamine is optionally protected.

Examples of R as alkyl are methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl and tert-butyl and as aryl or aralkyl are benzyl and naphthyl.

Preferred compounds of the invention have the formula

wherein A is defined as above, R₂ is hydrogen and R₁ is selected fromthe group consisting of

R_(a), R_(b), R_(c) and R_(d) are individually selected from the groupconsisting of alkyl of 1 to 18 carbon atoms, aryl and aryl of up to 18carbon atoms and mono- or polycyclic containing at least one heteroatomand X is selected from the group consisting of hydrogen, alkyl of 1 to 8carbon atoms and aryl of up to 14 carbon atoms or R₁ and R₂ togetherwith the nitrogen to which they are attached form a mono- or polycyclicwith at least one heteroatom.

Examples of cyclic protective groups are

A preferred compound of formula I has the formula

wherein R is alkyl of 1 to 8 carbon atoms, especially 1,1-dimethylethyl.

The process of the invention for the preparation of a compound offormula I comprises reacting a compound of the formula

in racemic form at the 6-member ring and R is as defined and above theamine is protected with a dehydrogenation agent to form thecorresponding compound of formula I.

Preferably, the starting material has the formula

wherein R, R₁ and R₂ have the above definitions and the dehydrogenationagent is a strong base, an oxidizing agent or a sulfur or seleniumderivative.

The compounds of formula II are racemic (SR+SS) at the level of the6-member ring and are novel products. They can be prepared by thefollowing process.

The starting compounds of the said process are described in or can beprepared as set forth in J. Chem. Soc. Perkins Trans. 1 (1979), Vol. 6,p. 1451-1454 Chem. Soc. Chem. Comm. (1977), p. 635-36.

The process of the invention for the preparation of a compound of theformula

wherein R is defined as above and the amine is optionally protectedcomprises reacting a compound of formula I with a reducing agent.

Preferably, the resulting compound has the formula

wherein R, R₁ and R₂ are defined as above and the reducing agent ishydrogen in the presence of Raney nickel, palladium on carbon, palladiumdihydroxide in the presence of talc, ruthenium on carbon or rhodium inthe presence of aluminum, more preferably hydrogen in the presence ofRaney nickel. The reaction is effected in the presence of a solvent suchas acetic acid, methanol, ethanol, isopropanol, dimethoxyethane,butanone, DMF or acetonitrile.

The compounds of formula IIIA are intermediates for the preparation ofpharmacological products such as the compounds described in EP PatentNo. 84,095 and in J. Chem. Soc. Perkin Trans. 1, (1986), p. 1011. Otherproducts of formula II are useful in a similar process.

The products of formula II and IIA in the SR form or the form of amixture (SR+SS) are novel intermediates as are the compounds of formulaIII and IIIA with the proviso that R is not hydrogen or tert.-butyl informula III and in formula IIIA, R is not hydrogen or tert.-butyl whenthe amine is protected by phthalimido. EP 94,095 describes a compound offormula IIIA when R is tert.-butyl and the amine is phthalimido.

In the following examples, there are described several preferredembodiments to illustrate the invention. However, it is to be understoodthat the invention is not intended to be limited to the specificembodiments.

PREPARATION 1 1,1-dimethyl-ethyl9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2-diazepine-1-carboxylate

Preparation a: 1-(benzyl) and 3-(1,1-dimethyl-ethyl)hexahydro-3-(2H)-pyridazinedicarboxylate

J. Chem. Soc. Chem. Comm. (1977) p. 635-636 or J. Chem. Soc. PerkinTrans. (1979) Vol 6. p. 1451-1454.

920 μl of BF₃-Et₂O and a solution of 18.85 g of terbutyltrichloroacetimidate, 45.5 ml of cyclohexane and 57.5 ml of dichloromethane were introduced at 20° C. into a suspension of 11.50 g of1,2-benzyl hexahydro-1,3(2H) pyridazinedicarboxylate and 115 ml ofdichloromethane. After isolation and purification treatment, theexpected product was obtained.

Preparation b: benzylγ-(chlorocarbonyl)-1,3-dioxo-1H-isoindole-2(3H)-butanoate

30 g of benzyl γ-carboxy-1,3-dioxo-1H-isoindol-(3H) -butanoate (EP94,095) were introduced, under a nitrogen atmosphere, into 81 ml ofterbutylmethylether. The reaction mixture was then cooled to 0°-2° C.and 17 g of phosphorus pentachloride were added. The reaction mixturewas allowed to return to ambient temperature and was stirred for 6hours, concentrated under reduced pressure, taken to 41° C. and the dryextract obtained was entrained using toluene. The product was held atambient temperature and under a nitrogen atmosphere, then diluted foruse in CH₂Cl₂, to obtain a 0.5 M solution of the desired product.

Stage A: 1-(benzyl)3-(1,1-dimethylethyl)-2-[1,5-dioxo-2-(1,3-dioxo-14-isoindol-2(3H)-yl-5-benzyloxy-pentyl]-tetrahydro-1,3-(2H)-pyridazinedicarboxylate

A 0.5 M solution of 52 ml of the product of Preparation b in, methylenechloride was cooled to 0°-1° C. and 5.6 g of the product of Preparationa and 22 ml of dichloromethane were added thereto. The reaction mixturewas stirred for 3 hours at 0°+1° C. and 1.77 ml of pyridine and 11 ml ofmethylene chloride were added. The dichloromethane was evaporated underreduced pressure at 30° C., followed by taking up in ethyl acetate,washing with aqueous solutions of sodium chloride and sodiumbicarbonate. Extraction was carried out with ethyl acetate, followed bydrying, rinsing and extracting under reduced pressure to obtain thedesired product which was chromatographed on silica and eluting with aheptane-ethyl acetate mixture 60-40 to obtain 4.697 g of the desiredproduct melting at ≦35° C.

Stage B: γ- [[3-[1,1-dimethylethoxy)carbonyl]-tetrahydro-2 (1H)-pyridazinyl]carbonyl]-1,3-dioxo-1H-isoindole-2- (3H) -butanoic acid

A mixture of 4.61 g of the product of Stage A and 47 ml oftetrahydrofuran was mixed at 20° C. and the reaction mixture washydrogenated at ambient temperature, using 400 mg of palladium on carbonas a catalyst. When the reaction was completed, the reaction mixture wasfiltered and rinsed with THF to obtain 2.76 g of the desired product.

Stage C: 1,1-dimethylethyl9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a]-1,2-diazepine-1-carboxylate

A solution of 0.846 ml of thionyl chloride in 2.6 ml of dichloromethanewas added at 0+2° C. to a mixture of 2.6 g of the product of Stage B, 26ml of methylene chloride and 50 μl of dimethylformamide. The reactionmixture was allowed to return to ambient temperature and was stirred for6 hours 20 minutes. The isolation and purification operations arecarried out to obtain the desired product.

EXAMPLE 1 1,1-dimethylethyl(9S),9-(1,3-dihydro-1,3-dioxopyridazino[1,2-a]-diazepine-1-carboxylate

a) Preparation of LDA

7.2 ml of butyllithium were added at about −60° over 10 minutes, under anitrogen atmosphere with stirring to a mixture of 20 ml of THF and 3.2ml of diisoopropylamine. The temperature was allowed to rise to 0° C.,was held for 1 hour at 0° C. and then was returned to −60° C.

b) Preparation of C₆H₅SeBr

0.26 of bromine were added at 10° C. to a solution of 1.88 g ofdiphenyldiselenium and 6 ml of THF. The reaction mixture was stirred for1 hour at 20° C.

c) Reaction

A mixture of 3.44 g of 1,2-dimethylethyl (1S-cis)9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a]-1,2-diazepine-1-carboxylatewas cooled at −65° C. and the solution of LDA prepared above was added.The reaction mixture was stirred for 10 minutes and the solution ofC₆H₅SeBr was added at a temperature of 60° C.±5° C. The temperature wasallowed to return to about 0° C. and 4 ml of water, 1.2 of ml of aceticacid and 4 ml of hydrogen peroxide were added. The temperature was,allowed to rise to 10° C. and the reaction mixture was stirred for 1hour. Then, 40 ml of a 10% aqueous solution of sodium chloride and 80 mlof ethyl acetate were added. The reaction mixture was decanted, washedwith a saturated solution of sodium chloride, and/or sodium bicarbonateat 10%, followed by evaporation under reduced pressure. The resultantmixture was chromatographed on silica, eluting with a methylenechloride-isopropyl ether mixture to obtain 1.3 g of the desired productwith a specific rotation of α_(D)=+126.5° C.=0.335/MeOH

Use: 1,1-dimethylethyl (1S-cis)9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-octahydro-6,10-dioxo-6H-pyridazino[1,2-a] [1,2]-diazepine-1-carboxylate

a) Preparation of the Catalyst

A mixture of 0.106 g of Raney nickel (Jansen) and 2 ml of sodiumhydroxide was stirred for 2 hours at 60° C. and the nickel was washedwith water. One drop of acetic acid was added to the last wash water andthe nickel was then washed with ethanol and ethyl acetate. The nickelobtained was kept under reduced pressure.

b) Reduction

3 ml of ethyl acetate were added to 0.053 g of nickel prepared aspreviously and 0.0485 g of the product of Example 1 was added to thesuspension obtained. The hydrogenation stage took place at ambienttemperature, until there was no further absorption of hydrogen. 2 ml ofhydrogen were absorbed and the product had a TLC rf=0.27 eluantisopropyl ether/methylene chloride (50—50).

Various modifications of the products and processes of the invention maybe made without departing from the spirit or scope thereof and it is tobe understood that the invention is intended to be limited only asdefined in the appended claims.

What we claim is:
 1. A compound of the formula

wherein R is selected from the group consisting of hydrogen, alkyl of 1to 4 carbon atoms and R₁ and R₂ form phthalimido with the nitrogen in SRform or in (SR+SS) mixture..
 2. A compound selected from the groupconsisting of the formulae

wherein R is alkyl of 1 to 4 carbon atoms, R₂ and R₁ with the nitrogenform phthalimido.
 3. A process for preparation of a compound of theformula

wherein R is selected from the group consisting of hydrogen, alkyl of 1to 18 carbon atoms and aryl and aralkyl of up to 18 carbon atoms and theamine is unprotected or protected comprising reacting a compound of theformula

where the amine is protected with a hydrogenation agent which is amixture of phenylselenium bromide, hydrogen peroxide and LDA.